ORIGINAL RESEARCH

Improved clinical outcome 3 months afterendovascular treatment, including thrombectomy, inpatients with acute ischemic stroke: a meta-analysisAnna Falk-Delgado,1,2 Åsa Kuntze Söderqvist,1,2 Jian Fransén,3

Alberto Falk-Delgado3,4

▸ Additional material ispublished online only. To viewplease visit the journal online(http://dx.doi.org/10.1136/neurintsurg-2015-011835).1Department of ClinicalNeuroscience, KarolinskaInstitute, Stockholm, Sweden2Department ofNeuroradiology, KarolinskaUniversity Hospital, Stockholm,Sweden3Department of SurgicalSciences, Plastic Surgery,Uppsala University, Uppsala,Sweden4Department of Plastic andMaxillofacial Surgery, UppsalaUniversity Hospital, Uppsala,Sweden

Correspondence toDr Alberto Falk-Delgado,Department of Plastic andReconstructive Surgery,Uppsala University Hospital,Ing 78/79, Akademiskasjukhuset, Uppsala 75185,Sweden;alberto.falk-delgado@surgsci.uu.se

AnF-D and AlF-D contributedequally.

Received 4 May 2015Accepted 29 May 2015

To cite: Falk-Delgado A,Kuntze Söderqvist Å,Fransén J, et al. JNeuroIntervent SurgPublished Online First:[please include Day MonthYear] doi:10.1136/neurintsurg-2015-011835

ABSTRACTBackground and purpose Intravenous thrombolysiswith tissue plasminogen activator is standard treatmentin acute stroke today. The benefit of endovasculartreatment has been questioned. Recently, studiesevaluating endovascular treatment and intravenousthrombolysis compared with intravenous thrombolysisalone, have reported improved outcome for theintervention group. The aim of this study was to performa meta-analysis of randomized controlled trialscomparing endovascular treatment in addition tointravenous thrombolysis with intravenous thrombolysisalone.Methods Databases were searched for eligiblerandomized controlled trials. The primary outcome was afunctional neurological outcome after 90 days.A secondary outcome was severe disability and death.Data were pooled in the control and intervention groups,and OR was calculated on an intention to treat basiswith 95% CIs. Outcome heterogeneity was evaluatedwith Cochrane’s Q test (significance level cut-off value at<0.10) and I2 (significance cut-off value >50%) withthe Mantel–Haenszel method for dichotomousoutcomes. A p value <0.05 was regarded as statisticallysignificant.Results Six studies met the eligibility criteria, and datafrom 1569 patients were analyzed. A higher probabilityof a functional neurological outcome after 90 days wasfound for the intervention group (OR 2, 95% CI 2 to 3).There was a significantly higher probability of death andsevere disability in the control group compared with theintervention group.Conclusions Endovascular treatment in addition tointravenous thrombolysis for acute ischemic stroke leadsto an improved clinical outcome after 3 months,compared with patients receiving intravenousthrombolysis alone.

INTRODUCTIONStroke is estimated to cause 5.7 million deaths glo-bally each year and to cause major disability inpatients who survive.1 An aging global populationhas increased the annual incidence of death fromischemic stroke by 50% from 1990 to 2013. Acutestroke treatment has undergone major changesduring the past decades.2 Currently, intravenoustissue plasminogen activator (tPA) within 3–4.5 h ofsymptom onset is an established treatment for ische-mic stroke and is associated with an improved func-tional outcome after 3 months. Endovascular

techniques of relieving vessel occlusion in acuteischemic stroke have been developed over the pastdecades and their clinical benefit has been ques-tioned.3 Endovascular treatment can mainly bedivided into loco-regional intra-arterial (IA) thromb-olysis and mechanical thrombectomy. A randomizedcontrolled trial (RCT) published in 1999 (Prolyse inAcute Cerebral Thromboembolism II (PROACT-II))showed improved clinical outcome in patientstreated with IA thrombolysis compared with IVheparin.4 However, the follow-up study, MiddleCerebral Artery Embolism Local FibrinolyticIntervention Trial (MELT), failed to prove a betteroutcome in patients treated with IA thrombolysis.5

An RCT by Ciccone et al6 (SYNTHESIS Expansion)comparing endovascular treatment (IA thrombolysisand mechanical thrombectomy) with IV thromboly-sis failed to show the superiority of endovasculartreatment. Kidwell et al7 (Mechanical Retrieval andRecanalization of Stroke Clots Using Embolectomy(MR RESCUE)), randomized patients to thrombec-tomy or standard medical care within 8 h fromstroke symptom onset and found no improved clin-ical outcome in the intervention group. Despite pre-vious discouraging results, new studies comparingfirst generation thrombectomy devices with moderngeneration of retrievable stents, favor the usage ofthe Trevo retriever and Solitaire flow restorationdevice compared with the older Merci retrievalsystem.8 9 Recently, studies evaluating endovasculartreatment and IV thrombolysis compared with IVthrombolysis alone showed improved outcome forthe intervention group.10–12

Clinical outcome of stroke patients can be assessedusing the modified Rankin Scale (mRS). mRS scoresrange from 0 to 6, and a score of 0 indicates nosymptoms, 1=no significant disability, 2=slight dis-ability, 3=moderate disability, 4=moderately severedisability, 5=severe disability, and 6=death. A scorebetween 0 and 1 reflects an excellent outcome and ascore of 0–2 a functional outcome.13

A meta-analysis by Fargen et al14 showedimproved outcome for endovascular treatmentcompared with medical management in acute ische-mic stroke. Since the publication of this recentmeta-analysis, several new RCTs have been pub-lished, highlighting the need for an updatedmeta-analysis in the field of neurointerventionaltreatment in acute ischemic stroke.The aim of this study was to perform a

meta-analysis of current eligible RCTs comparing

Falk-Delgado A, et al. J NeuroIntervent Surg 2015;0:1–7. doi:10.1136/neurintsurg-2015-011835 1

Ischemic stroke on M

ay 27, 2020 by guest. Protected by copyright.

http://jnis.bmj.com

/J N

euroIntervent Surg: first published as 10.1136/neurintsurg-2015-011835 on 2 July 2015. D

ownloaded from

endovascular treatment in addition to IV thrombolysis with IVthrombolysis alone, in order to evaluate and quantify the aggre-gated benefit for mechanical thrombectomy in acute ischemicstroke.

METHODSEligibility criteriaOnly RCTs were considered for inclusion. The interventiongroup was endovascular treatment in addition to IV thromboly-sis, and the control group was IV thrombolysis. Only completestudies published in whole were included. Only studies with atleast two-thirds of all participants receiving IV thrombolysiswere considered for inclusion. There were no restrictions instudy language, study age, included patient age, imaging criteria,or National Institutes of Health Stroke Scale (NIHSS) score.

Information sourceWe searched PubMed, the Cochrane Central Register ofControlled Trials, and the National Institutes of Health ClinicalTrials from the date of inception until 17 April 2015. Twosearches were performed. The first search terms were ‘thromb-ectomy’ and ‘thrombolysis’; the second search terms were‘endovascular treatment’, ‘stroke’, and ‘randomized’. All manu-script titles were assessed and eligible abstracts were read.Manuscripts to be read in whole were selected from abstractsthat fulfilled the inclusion criteria. Manuscripts found in refer-ences lists from read manuscripts were also assessed for possibleinclusion. Two independent reviewers assessed the retrievedmanuscripts for possible inclusion in the meta-analysis. Any dis-agreements were resolved by discussion.

Data collection processTwo independent reviewers extracted data from the includedstudies from the published manuscripts, study protocols, andappendices. The primary specified outcome was the proportionof patients with an mRS score of 0–2 at 90 days from strokeonset. Secondary outcomes included mRS 0–1 at 90 days, mRS0–3 at 90 days, mortality at 90 days, intracerebral hemorrhagewithin 90 days, and mRS 5–6 at 90 days. To maintain highhomogeneity between the included studies, a subgroup ofpatients in the Interventional Management of Stroke-III(IMS-III) trial that did not have vessel occlusion on imagingwere excluded from further analysis. Data were treated accord-ing to the intention to treat analysis, and randomized patientsremained in their first allocated treatment arm in the outcomeanalysis. Data from patients lost to follow-up were imputed withmRS 5 in order not to overestimate the treatment effect instudies with a higher percentage of dropouts.

Statistical analysisTwo independent reviewers performed the statistical analyses(Review Manager, RevMan, V.5.3., Copenhagen, The NordicCochrane Centre, The Cochrane Collaboration, 2014). ReviewManager was used for data presentation. Data were pooled inthe intervention group and the control group. Outcome hetero-geneity was evaluated with Cochrane’s Q test (significance levelcut-off value at <0.10) and I2 (significance cut-off value>50%). A p value <0.05 was considered statistically significant.The Mantel–Haenszel method was used for dichotomous out-comes with fixed effect or random effect (DerSimonian andLaird15) where appropriate, according to outcome heterogen-eity. OR with 95% CI were calculated for all outcomes.

RESULTSSearch findingsA total of 2138 articles were identified; 1942 articles did notmatch the eligibility criteria. One hundred and ninety-sixabstracts were eligible for evaluation and 22 of these wereselected for full text evaluation. Of the 22 manuscripts analyzedin full text, 11 were not RCTs and hence were excluded. FiveRCTs were further excluded for various reasons. The study ofMiao et al16 was excluded as patients did not receive IV thromb-olysis. In two studies (Solitaire with the Intention forThrombectomy (SWIFT) study by Saver et al8 and Trevo versusMerci retrievers for thrombectomy revascularization of largevessel occlusions in acute ischemic stroke (TREVO 2) byNogueira et al9) patients were randomized to different endovas-cular treatments with no control group receiving IV thromboly-sis. The intervention group in the SYNTHESIS Expansion trialdid not receive systemic thrombolysis.6 MR RESCUE wasexcluded as <50% of the included patients received systemicthrombolysis.7 The remaining six articles met all of the eligibilitycriteria and hence were included in the meta-analysis.10–12 17–19

Randomized controlled trialsAll trials were randomized 1:1, except IMS-III, which was rando-mized 2:1, with more patients in the intervention group. Alltrials were prospective randomized, open label, blinded end-point with intention to treat analyses. Extending the Time forThrombolysis in Emergency Neurological Deficits-Intra-Arterial(EXTEND-1A) also included target group analysis. Study qualitydetails are presented in the online supplementary table S1.

Study characteristicsIn total, the six RCTs randomized 1943 patients to either theintervention group (55%) or the control group (45%). Studycharacteristics are shown in table 1.

Time to inclusion from symptom onset varied between <3 hin the IMS-III trial to <12 h in the Endovascular Treatment forSmall Core and Anterior Circulation Proximal Occlusion withEmphasis on Minimizing CT to Recanalization Times (ESCAPE)trial.10 Five of the six studies included patients with strokesymptoms from the anterior circulation. All studies requiredimaging of vessel occlusion status before inclusion, except theIMS-III trial. In the IMS-III trial, 284 patients had been rando-mized before CT angiography was allowed in the study. Wetherefore decided to perform a post hoc analysis including onlypatients with baseline CTangiography and vessel occlusion fromthe IMS-III trial.20

Study designIn all studies both the intervention group and the control groupreceived IV tPA if eligible. Time from symptom onset to treat-ment with IV thrombolysis varied from <3 h in IMS-III to<4.5 h in the other trials. In Randomized Trial ofRevascularization with Solitaire FR Device versus Best MedicalTherapy in the Treatment of Acute Stroke Due to AnteriorCirculation Large Vessel Occlusion Presenting within EightHours of Symptom Onset (REVASCAT), patients presentingwith acute stroke without signs of revascularization after 30 minof IV tPA, or patients not eligible for IV tPA, received eitherthrombectomy or medical care.

Patient characteristicsA detailed description of the patients in each trial, divided intoan experimental group and a control group, is presented in the

2 Falk-Delgado A, et al. J NeuroIntervent Surg 2015;0:1–7. doi:10.1136/neurintsurg-2015-011835

Ischemic stroke on M

ay 27, 2020 by guest. Protected by copyright.

http://jnis.bmj.com

/J N

euroIntervent Surg: first published as 10.1136/neurintsurg-2015-011835 on 2 July 2015. D

ownloaded from

Table 1 Study details

Study name Trial period Location

Enrolledcenters(n)

Studydesign

Randomizedpatients (n) Intervention Control

Inclusioncriterion:NIHSS

Inclusioncriterion:age (years)

Inclusioncriterion:occluded vessel Stroke imaging Primary outcome Safety measures

ESCAPE 2013−2014 Canada, USA,South Korea,Europe

22 RCT 316 IV tPA if eligible plusendovascular treatment

IV tPA ifeligible

>5 ≥18 Middle cerebralartery with orwithout occlusionof the internalcarotid artery

Non-contrast CTand CTA,multiphase CT

mRS after 90 days Mortality andother

EXTEND-1A 2012−2014 Australia, NewZealand

10 RCT 70 IV tPA if eligible plusendovascularthrombectomy

IV tPA ifeligible

0−42 ≥18 Internal carotidartery or middlecerebral artery andmismatch on CTperfusion or MR

Non-contrast CT,CTA/MRA and CTperfusion ordiffusion MRI

Reperfusion atimaging after24 h, earlyneurologicimprovement

Mortality.Symptomaticintracranialhematoma

IMS-III 2006−2012 USA, Canada,Australia,Europe

58 RCT 656 IV tPA if eligible plusendovascular treatment

IV tPA ifeligible

≥10* 18−82 Anterior orposteriorcirculation

Non contrast CT,CTA†

mRS ≤2 after90 days

Mortality within90 days,symptomatic ICHwithin 24±6 h

MR CLEAN 2010−2014 Europe 16 RCT 502 IV tPA if eligible plusintra-arterial treatmentwith thrombolysis ormechanicalthrombectomy, or both

IV tPA ifeligible

≥2 ≥18 Distal carotidartery, middle oranterior cerebralartery

Non-contrast CT orMRI. CTA/MRA/DSA

mRS ≤2 after90 days

Neurologicdeteriorationwithin 24 h frominclusion in thestudy

SWIFT-PRIME 2012−2014 USA, Europe 39 RCT 196 IV tPA plus endovascularthrombectomy

IV tPA ≥8 and <30 18−80 Distal carotidartery or middlecerebral artery

Non-contrast CT orMRI. CTA/MRA

mRS after 90 days Mortality within90 days

REVASCAT 2012−2014 Europe 4 RCT 206 IV tPA if eligible plusendovascularthrombectomy

IV tPA ≥6 18−85 (80)‡ Middle cerebralartery with orwithout occlusionof the internalcarotid artery

Non-contrast CT orMRI. CTA/MRA orangiogram

mRS after 90 days Mortality within90 days

*NIHSS >7 if occlusion of M1, internal carotid artery, or basilar artery on CTA at institutions where baseline CTA imaging is standard of care for acute stroke patient. Baseline CTA in n=306. No baseline CTA in n=350.†Arterial occlusion on CTA or MRA of the internal carotid artery, M1, or M2. CTA was performed in 306 of 656 patients and mismatch, using CT or MRI, with a Tmax above 6 s delay perfusion volume and either CT-regional cerebral blood flow ordiffusion weighted imaging infarct core volume.‡After enrollment of 160 patients, the inclusion criteria were modified to include patients up to the age of 85 years with an Alberta Stroke Program Early CT score of >8.Studies: ESCAPE, Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times; EXTEND, Extending the Time for Thrombolysis in Emergency Neurological Deficits; IMS-III,Interventional Management of Stroke-III; MR CLEAN, Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands; REVASCAT, Randomized Trial of Revascularization with Solitaire FR Device versus BestMedical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset; SWIFT-PRIME, Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment;CTA, CT angiography; DSA, digital subtraction angiography; ICH, intracerebral hemorrhage; IV tPA, intravenous tissue plasminogen activator; MRA, MR angiography; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale;RCT, randomized controlled trial.

Falk-DelgadoA,etal.J

NeuroInterventSurg

2015;0:1–7.doi:10.1136/neurintsurg-2015-011835

3

Ischemic

stroke on May 27, 2020 by guest. Protected by copyright. http://jnis.bmj.com/ J NeuroIntervent Surg: first published as 10.1136/neurintsurg-2015-011835 on 2 July 2015. Downloaded from

online supplementary table S2. Median or mean age of thepatients in all groups varied from 65 to 71 years. MedianNIHSS score (0–42, higher score indicates more severe strokesymptoms) was 13–18. The intervention group received endo-vascular treatment if eligible (77% in EXTEND-1A to 100% inIMS-III). Full intervention group characteristics are presented intable 2.

Control group characteristics are presented in the onlinesupplementary table S3. Overall, all patients in Solitaire withthe Intention for Thrombectomy as Primary EndovascularTreatment (SWIFT PRIME), EXTEND-1A, and the subgroup ofpatients in IMS-III with vessels occlusion received IV thromb-olysis. The percentages receiving IV thrombolysis in the otherthree studies varied between 78% and 91% in the controlgroups and between 68% and 87% in the intervention groups.

Primary and secondary outcomesThe primary outcome measure, mRS score of 0–2 at 90 daysfrom symptom onset, was favored in the intervention group.The proportion of patients with mRS 0–2 after 90 days was46% in the intervention group and 27% in the control group(figure 1A). The absolute risk reduction for the interventiongroup compared with the control group was 19% (95% CI 14%to 23%). Number needed to treat for mRS 0–2 in the interven-tion group was 6 (95% CI 4 to 7). Results from analyses of sec-ondary outcomes showed a significantly increased proportion ofpatients in the intervention group with an excellent outcome(mRS 0–1, figure 1B) and of mRS 0–3 after 90 days. There wasa significantly reduced risk of mortality in the interventiongroup compared with the control group, with an absolute riskreduction for death of 4% (95% CI 1% to 8%) in the interven-tion group. The number needed to treat in the interventiongroup to avoid one death was 23 (95% CI 12 to 149). Therewas a significantly higher probability for severe disability anddeath in the control group (table 3). There were no differencesregarding symptomatic intracerebral hemorrhage between theintervention and control groups. To more specifically evaluatethe effect of stent retrievers on stroke outcome, we performed asensitivity analysis excluding the IMS-III trial due to its limitedused of stent retrievers. In general, the outcomes for the inter-vention group improved after exclusion of the IMS-III trial(figure 1C, D). The proportion with a functional outcome (mRS0–2) in the intervention group was 47% and 26% in the control

group, with an absolute risk reduction of 21% (95% CI 15% to26%) in the intervention group and a number needed to treatof five patients (95% CI 4 to 7). There was no statistically sig-nificant differences in mortality or intracerebral hemorrhagebetween the intervention and control groups in the sensitivityanalysis. Comparisons between the outcomes are presented intable 4.

DISCUSSIONIn this meta-analysis, we analyzed six RCTs with 1569 patients,evaluating the outcome in patients with acute ischemic strokewith a documented occlusion who received either IV thromb-olysis (control) or IV thrombolysis plus endovascular treatment(intervention group).

The aim of this meta-analysis was to evaluate the role ofendovascular treatment, in particular for stent retrievers, inacute ischemic stroke. Our results indicate that treatment withendovascular treatment, including mechanical thrombectomy,leads to a higher ratio of patients with an improved clinicaloutcome after 3 months from stroke onset compared with thecontrol group receiving IV thrombolysis alone. Patients receivingIV thrombolysis alone had a higher probability of mRS 5–6 anddeath after 3 months; this has not been shown in previoussingle RCTs. However, this was not significant when the IMS-IIItrial was excluded.

There were a number of differences between the six trials. TheIMS-III trial included patients over 8 years and used several dif-ferent devices for mechanical thrombectomy, due to the techno-logical and scientific evolution of stent retrievers during the studyperiod.8 9 Percentages of patients in the intervention groups thatreceived mechanical thrombectomy varied between trials. In theIMS-III trial, only 39% received mechanical thrombectomy inthe intervention group. This was due to inclusion of patientswithout a CT angiography verified vessel occlusion. After con-firmed vessel occlusion on CTangiography was used as an inclu-sion criterion, all patients in the intervention group receivedendovascular treatment. This was adjusted for in our analysis byusing patients from the cohort of CT angiography verified vesselocclusions. Study heterogeneity decreased after inclusion of onlyCT angiography confirmed vessel occlusion from the IMS-IIItrial. There was wide use of stent retrievers among the RCTs,except for the IMS-III trial. To more specifically evaluate clinicaloutcome after treatment with stent retrievers in combination

Table 2 Intervention group characteristics

Study name

Allocated tointerventiongroup (n)

Receivedendovasculartherapy (n (%))

ReceivedIA tPA (n (%))

Mechanicalthrombectomy(n (%))

Time fromonset to groinpuncture (min)

mTICI of≥2b (n)*

Treatmentwith IVtPA (n (%))

ESCAPE 165 151 (92) NA 151 (92) 75† 113 120 (73)EXTEND-1A 35 27 (77) 0 27 (77) 210 25 35 (100)IMS-III‡ 190 190 (100) NA NA NA 86§ 190 (100)MR CLEAN 233 196 (84) 24 (10) 195 (84) 260 115 203 (87)SWIFT-PRIME 98 87 (89) NA 87 (89) 224 73 98 (100)REVASCAT 103 98 (95) 1 (0) 98 (95) 269 67 70 (68)

* mTICI score between 0 and 3; 0 is no perfusion and 3 is complete reperfusion. A score of ≥2b is considered successful reperfusion.†Time from randomization to groin puncture.‡Subgroup with CT angiography verified vessel occlusion.§Successful recanalization was defined as grade 3–5 flow in previously occluded (grade 1–2) segments of symptomatic intracranial arteries on 24 h CT angiography and/or MRangiography.Studies: ESCAPE, Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times; EXTEND, Extending theTime for Thrombolysis in Emergency Neurological Deficits; IMS-III, Interventional Management of Stroke-III; MR CLEAN, Multicenter Randomized Clinical Trial of EndovascularTreatment for Acute Ischemic Stroke in The Netherlands; REVASCAT, Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment ofAcute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset; SWIFT-PRIME, Solitaire with the Intention for Thrombectomy asPrimary Endovascular Treatment.IA tPA, intra-arterial tissue plasminogen activator; mTICI, modified Thrombolysis in Cerebral Infarction; NA, assessed.

4 Falk-Delgado A, et al. J NeuroIntervent Surg 2015;0:1–7. doi:10.1136/neurintsurg-2015-011835

Ischemic stroke on M

ay 27, 2020 by guest. Protected by copyright.

http://jnis.bmj.com

/J N

euroIntervent Surg: first published as 10.1136/neurintsurg-2015-011835 on 2 July 2015. D

ownloaded from

Figure 1 Forest plot of the modified Rankin Scale (mRS) in the intervention and control groups. (A) OR of mRS 0–2 (functional outcome) in theintervention and control groups after 90 days. (B) OR of mRS 0–1 (excellent outcome) in the intervention and control groups after 90 days. (C) OR ofmRS 0–2 (functional outcome) in the intervention and control groups after 90 days, excluding IMS-III. (D) OR of mRS 0–1 (excellent outcome) in theintervention and control groups after 90 days, excluding IMS-III. Studies: ESCAPE, Endovascular Treatment for Small Core and Anterior CirculationProximal Occlusion with Emphasis on Minimizing CT to Recanalization Times; EXTEND, Extending the Time for Thrombolysis in EmergencyNeurological Deficits; IMS-III, Interventional Management of Stroke-III; MR CLEAN, Multicenter Randomized Clinical Trial of Endovascular Treatmentfor Acute Ischemic Stroke in The Netherlands; REVASCAT, Randomized Trial of Revascularization with Solitaire FR Device versus Best MedicalTherapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset;SWIFT-PRIME, Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment.

Table 3 Outcome 90 days after stroke symptom onset comparing the intervention and control groups*

Outcome Endovascular group (n (%)) Control group (n (%)) OR (95% CI) p Value

mRS 0–2 (functional outcome) 380 (46) 205 (28) 2.21 (1.78 to 2.74) <0.00001mRS 0–1 (excellent outcome) 235 (29) 101 (14) 2.46 (1.89 to 3.22) <0.00001mRS 0–3 509 (62) 320 (43) 2.15 (1.75 to 2.64) <0.00001Mortality 125 (15) 146 (20) 0.73 (0.56 to 0.96) 0.02Symptomatic intracerebral hemorrhage 41 (5) 34 (5) 1.05 (0.65 to 1.68) 0.85mRS 5–6 188 (23) 249 (33) 0.58 (0.46 to 0.73) <0.00001

*Subgroup from IMS-III with CT angiography verified vessel occlusion.IMS-III, Interventional Management of Stroke-III; mRS, modified Rankin Scale score.

Falk-Delgado A, et al. J NeuroIntervent Surg 2015;0:1–7. doi:10.1136/neurintsurg-2015-011835 5

Ischemic stroke on M

ay 27, 2020 by guest. Protected by copyright.

http://jnis.bmj.com

/J N

euroIntervent Surg: first published as 10.1136/neurintsurg-2015-011835 on 2 July 2015. D

ownloaded from

with thrombolysis, we compared the five included RCTs afterexclusion of the IMS-III trial in a sensitivity analysis. Excludingthe IMS-III trial yielded a higher OR for functional and excellentoutcome after 3 months, and a higher probability for a pooroutcome (mRS 5–6) in the control group.

Time to intervention varied between included studies, withlonger time to intervention in REVASCAT and MulticenterRandomized Clinical Trial of Endovascular Treatment for AcuteIschemic Stroke in The Netherlands (MR CLEAN). Poorerresult in clinical outcome in these two studies compared withESCAPE, EXTEND, and SWIFT PRIME might be attributed tolonger time to reperfusion and higher proportion of patientswith successful recanalization, and emphasizes the importanceof time in acute stroke care.

The generalizability of these results requires some caution.Included patients in these trials were a highly selected groupand represent a small fraction of all stroke patients. Only 5–13% of all stroke patients present to hospital within the timewindow for thrombolysis. Contraindications for IV thrombolysisfurther reduce the number of eligible patients.21 For example, atotal of 7798 patients presented with acute ischemic stroke andwere assessed for eligibility in the EXTEND-1A trial; 1044 ofthese received IV tPA, but only 70 patients were enrolled in thestudy. Major reasons for exclusion after treatment with systemicthrombolysis was lack of occlusion of a major vessel, out ofoperating hours, or poor premorbid condition.

Five of the six included studies were stopped early. Prematurestop because of efficacy has been shown to have a risk of resultoverestimation of the effect size and hence requires a certaindegree of caution when interpreting the results.22

A limitation of this meta-analysis is the lack of individualpatient data for patients lost to follow-up, which might affectthe results of the outcome analyses. Lack of individual patientdata limits the possibility of subgroup analyses of patients withdifferent clinical characteristics. Secondly, no specific search ofunpublished studies was performed, possibly introducing a riskof publication bias. Although all included studies were of highscientific quality, the risk of bias due to funding from industrygrants is not negligible. Considering that five of the six RCTsonly included occlusions in the anterior circulation, this mightalso limit the generalizability of the results to patients withischemic stroke in the posterior circulation. Furthermore, longtime follow-up from these RCTs needs to be assessed in orderto evaluate the treatment benefits after 3 months.

In addition to the six included RCTs, preliminary results fromthe Trial and Cost Effectiveness Evaluation of Intra-arterialThrombectomy in Acute Ischemic Stroke (THRACE) trial havebeen presented.23 This is a French multicentre study including,to date, 385 patients. Patients were randomized during IVthrombolysis treatment into intervention or no additional

treatment. Including these results in the meta-analysis yields anOR for functional outcome of 2 (95% CI 1 to 3), favoring inter-vention, with a numbers needed to treat of 8 (95% CI 6 to 10).

ConclusionPatients with acute stroke treated with IV thrombolysis and add-itional endovascular treatment with mechanical thrombectomyshow improved functional outcome and lower mortality after3 months from stroke onset compared with patients receivingIV thrombolysis alone.

Contributors AnF-D and AlF-D contributed equally to this study. AnF-D and AlF-Dplanned the work, and were responsible for data collection, analysis, andinterpretation, and writing of the manuscript. JF performed the statistical analysisand critically revised the content. ÅKS interpreted the data and critically revised themanuscript. All authors approved the final version and agreed on the integrity of thework.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

Open Access This is an Open Access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-NC 4.0) license, whichpermits others to distribute, remix, adapt, build upon this work non-commercially,and license their derivative works on different terms, provided the original work isproperly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

REFERENCES1 Strong K, Mathers C, Bonita R. Preventing stroke: saving lives around the world.

Lancet Neurol 2007;6:182–7.2 Roth GA, Forouzanfar MH, Moran AE, et al. Demographic and epidemiologic drivers

of global cardiovascular mortality. N Engl J Med 2015;372:1333–41.3 Qureshi AI, Abd-Allah F, Aleu A, et al. Endovascular treatment for acute ischemic

stroke patients: implications and interpretation of IMS III, MR RESCUE, andSYNTHESIS EXPANSION trials: a report from the Working Group of InternationalCongress of Interventional Neurology. J Vasc Interv Neurol 2014;7:56–75.

4 Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acuteischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse inAcute Cerebral Thromboembolism. JAMA 1999;282:2003–11.

5 Ogawa A, Mori E, Minematsu K, et al. Randomized trial of intraarterial infusion ofurokinase within 6 hours of middle cerebral artery stroke: the middle cerebral arteryembolism local fibrinolytic intervention trial (MELT) Japan. Stroke J Cereb Circ2007;38:2633–9.

6 Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acuteischemic stroke. N Engl J Med 2013;368:904–13.

7 Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection andendovascular treatment for ischemic stroke. N Engl J Med 2013;368:914–23.

8 Saver JL, Jahan R, Levy EI, et al. Solitaire flow restoration device versus the Merciretriever in patients with acute ischaemic stroke (SWIFT): a randomised,parallel-group, non-inferiority trial. Lancet 2012;380:1241–9.

9 Nogueira RG, Lutsep HL, Gupta R, et al. Trevo versus Merci retrievers forthrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke(TREVO 2): a randomised trial. Lancet 2012;380:1231–40.

10 Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapidendovascular treatment of ischemic stroke. N Engl J Med 2015;372:1019–30.

11 Campbell BCV, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemicstroke with perfusion-imaging selection. N Engl J Med 2015;372:1009–18.

Table 4 Outcome 90 days after stroke symptom onset comparing the intervention and control groups, excluding IMS-III

Outcome Endovascular group (n (%)) Control group (n (%)) OR (95% CI) p Value

mRS 0–2 (functional outcome) 295 (47) 170 (26) 2.48 (1.95 to 3.15) <0.00001mRS 0–1 (excellent outcome) 172 (27) 83 (13) 2.59 (1.92 to 3.48) <0.00001mRS 0–3 400 (63) 275 (42) 2.34 (1.87 to 2.94) <0.00001Mortality 97 (15) 122 (19) 0.80 (0.60 to 1.08) 0.14Symptomatic intracerebral hemorrhage 26 (4) 28 (4) 1.00 (0.58 to 1.71) 0.99mRS 5–6 139 (22) 217 (33) 0.57 (0.44 to 0.73) <0.00001

IMS-III, Interventional Management of Stroke-III; mRS, modified Rankin Scale score.

6 Falk-Delgado A, et al. J NeuroIntervent Surg 2015;0:1–7. doi:10.1136/neurintsurg-2015-011835

Ischemic stroke on M

ay 27, 2020 by guest. Protected by copyright.

http://jnis.bmj.com

/J N

euroIntervent Surg: first published as 10.1136/neurintsurg-2015-011835 on 2 July 2015. D

ownloaded from

12 Berkhemer OA, Fransen PSS, Beumer D, et al. A randomized trial of intraarterialtreatment for acute ischemic stroke. N Engl J Med 2015;372:11–20.

13 Van Swieten JC, Koudstaal PJ, Visser MC, et al. Interobserver agreement forthe assessment of handicap in stroke patients. Stroke J Cereb Circ 1988;19:604–7.

14 Fargen KM, Neal D, Fiorella DJ, et al. A meta-analysis of prospective randomizedcontrolled trials evaluating endovascular therapies for acute ischemic stroke.J Neurointerventional Surg 2015;7:84–9.

15 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–88.16 Miao Z, Jiang L, Wu H, et al. Randomized controlled trial of symptomatic middle

cerebral artery stenosis: endovascular versus medical therapy in a Chinesepopulation. Stroke 2012;43:3284–90. 0

17 Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy afterintravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013;368:893–903.

18 Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 hours after symptomonset in ischemic stroke. N Engl J Med 2015. doi:10.1056/NEJMoa1503780

19 Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenoust-PA vs. t-PA alone in stroke. N Engl J Med 2015. doi:10.1056/NEJMoa1415061

20 Demchuk AM, Goyal M, Yeatts SD, et al. Recanalization and clinical outcome ofocclusion sites at baseline CT angiography in the interventional management ofstroke III trial. Radiology 2014;273:202–10.

21 Zahuranec DB, Majersik JJ. Percentage of acute stroke patients eligible forendovascular treatment. Neurology 2012;79:S22–5.

22 Bassler D, Briel M, Montori VM, et al. Stopping randomized trials early for benefitand estimation of treatment effects: systematic review and meta-regression analysis.JAMA 2010;303:1180–7.

23 Bracard S, Ducrocq X, Guillemin F. THRACE STUDY:Intermediate analysis results.European Stroke Organization Conference; 18 Apr 2015, Glasgow, Scotland.

Falk-Delgado A, et al. J NeuroIntervent Surg 2015;0:1–7. doi:10.1136/neurintsurg-2015-011835 7

Ischemic stroke on M

ay 27, 2020 by guest. Protected by copyright.

http://jnis.bmj.com

/J N

euroIntervent Surg: first published as 10.1136/neurintsurg-2015-011835 on 2 July 2015. D

ownloaded from